Crystal forms of (r)-n-methylnaltrexone bromide and uses thereof

ABSTRACT

The present invention provides a new forms of (R)—N-methylnaltrexone, and compositions thereof, useful as a peripheral mu opioid receptor antagonist.

BACKGROUND OF THE INVENTION

Opioids are widely used in patients with advanced cancers and otherterminal diseases to lessen suffering. Opioids are narcotic medicationsthat activate opioid receptors located in the central nervous system torelieve pain. Opioids, however, also react with receptors outside of thecentral nervous system, resulting in side effects includingconstipation, nausea, vomiting, urinary retention, and severe itching.Most notable are the effects in the gastrointestinal tract (GI) whereopioids inhibit gastric emptying and propulsive motor activity of theintestine, thereby decreasing the rate of intestinal transit andproducing constipation. The effectiveness of opioids for pain is oftenlimited due to resultant side effects, which can be debilitating andoften cause patients to cease use of opioid analgesics.

In addition to analgesic opioid induced side effects, studies havesuggested that endogenous opioid compounds and receptors may also affectactivity of the gastrointestinal (GI) tract and may be involved innormal regulation of intestinal motility and mucosal transport of fluidsin both animals and man. (Koch, T. R, et al, Digestive Diseases andSciences 1991, 36, 712-728; Schuller, A. G. P., et al., Society ofNeuroscience Abstracts 1998, 24, 524, Reisine, T., and Pasternak, G.,Goodman & Gilman's The Pharmacological Basis of Therapeutics NinthEdition 1996, 521-555 and Bagnol, D., et al., Regul. Pept. 1993, 47,259-273). Thus, an abnormal physiological level of endogenous compoundsand/or receptor activity may lead to bowel dysfunction.

For example, patients who have undergone surgical procedures, especiallysurgery of the abdomen, often suffer from a particular boweldysfunction, called post-operative (or post-surgical) ileus, that may becaused by fluctuations in natural opioid levels. Similarly, women whohave recently given birth commonly suffer from post-partum ileus, whichis thought to be caused by similar natural opioid fluctuations as aresult of birthing stress. Gastrointestinal dysfunction associated withpost-operative or post partum ileus can typically last for 3 to 5 days,with some severe cases lasting more than a week. Administration ofopioid analgesics to a patient after surgery, which is now an almostuniversal practice, may exacerbate bowel dysfunction, thereby delayingrecovery of normal bowel function, prolonging hospital stays, andincreasing medical care costs.

Opioid receptor antagonists such as naloxone, naltrexone, and nalmefene,have been studied as a means of antagonizing undesirable peripheraleffects of opioids. However, these agents act not only on peripheralopioid receptors, but also on central nervous system sites, so that theysometimes reverse the beneficial analgesic effects of opioids, or causesymptoms of opioid withdrawal. Preferable approaches for use incontrolling opioid-induced side effects include administration ofperipheral opioid receptor antagonist compounds that do not readilycross the blood-brain barrier. For example, the peripheral μ opioidreceptor antagonist compound methylnaltrexone and related compounds havebeen disclosed for use in curbing opioid-induced side effects inpatients (e.g., constipation, pruritus, nausea, and/or vomiting). See,e.g., U.S. Pat. Nos. 5,972,954, 5,102,887, 4,861,781, and 4,719,215; andYuan, C. -S. et al. Drug and Alcohol Dependence 1998, 52, 161.Similarly, peripherally selective piperidine-N-alkylcarboxylate and3,4-dimethyl-4-aryl-piperidine opioid receptor antagonists have beendescribed as being useful for treatment of opioid-induced side effectsconstipation, nausea or vomiting, as well as irritable bowel syndromeand idiopathic constipation. See, e.g., U.S. Pat. Nos. 5,250,542,5,434,171, 5,159,081, and 5,270,328.

It would be desirable to provide peripheral μ opioid receptor antagonistcompounds in a form suitable for administration to a patient in need oftreatment for any of the above-mentioned disorders.

SUMMARY

The present invention provides solid forms of Compound 1, a peripheral μopioid receptor antagonist:

where the compound is in the (R) configuration with respect to thenitrogen. The present invention also provides pharmaceuticalcompositions and formulations comprising such solid forms. Compound 1,and inventive solid forms thereof, is useful for the treatment,prevention, amelioration, delay or reduction of severity and/orincidence of side effects associated with opioid administration, suchas, for example, gastrointestinal dysfunction (e.g., inhibition ofintestinal motility, constipation, GI sphincter constriction, nausea,emesis (vomiting), biliary spasm, opioid bowel dysfunction, colic),dysphoria, pruritus, urinary retention, depression of respiration,papillary constriction, cardiovascular effects, chest wall rigidity andcough suppression, depression of stress response, and immune suppressionassociated with administration of narcotic analgesia, etc, orcombinations thereof. Other uses of Compound 1, and inventive solidforms thereof as described herein, are set forth infra.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts the X-Ray Powder Diffraction pattern for Form A.

FIG. 1B depicts the X-Ray Powder Diffraction pattern for Form A,calculated for single crystal data collected at a temperature of 150±1degrees K.

FIG. 2 depicts the DSC and TO overlay for Form A.

FIG. 3 depicts the X-Ray Powder Diffraction pattern for amorphousCompound 1.

FIG. 4 depicts the X-Ray Powder Diffraction pattern for Form B.

FIG. 5 depicts the DSC and TG overlay for Form B.

FIG. 6 depicts the X-Ray Powder Diffraction pattern for Form D.

FIG. 7 depicts the DSC and TG overlay for Form D.

FIG. 8 depicts the X-Ray Powder Diffraction pattern for Form C,calculated for single crystal data collected at a temperature of 150±1degrees K.

FIG. 9 depicts the X-Ray Powder Diffraction pattern for a mixture ofForm A+Form C (preferred orientation).

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION GeneralDescription of Certain Aspects of the Invention:

International patent application publication number WO2006/127899describes Compound 1, (R)—N-methylnaltrexone bromide, which has thefollowing structure:

where the compound is in the (R) configuration with respect to thenitrogen. In certain embodiments of the present invention, at leastabout 99.6%, 99.7%, 99.8%, 99.85%, 99.9%, or 99.95% of Compound 1 is inthe (R) configuration with respect to nitrogen. Methods for determiningthe amount of (R)—N-methylnaltrexone bromide, present in a sample ascompared to the amount of (S)—N-methylnaltrexone bromide present in thatsame sample, are described in detail in WO2006/127899, the entirety ofwhich is hereby incorporated herein by reference. In other embodiments,Compound 1 contains 0.15% or less (S)—N-methylnaltrexone bromide. Instill other embodiments, Compound 1 contains 0.10% or 0.05% or less(S)—N-methylnaltrexone bromide.

Compound 1, also known as “(R)-MNTX,” exhibits peripheral μ opioidreceptor antagonist activity in therapeutic models. Accordingly,Compound 1 is useful for antagonizing undesirable side effects of opioidactivity, including those associated with opioid analgesic therapy(e.g., gastrointestinal effects (e.g., delayed gastric emptying, alteredGI tract motility), etc.). In certain embodiments of the presentinvention, Compound 1 is useful for the treatment, prevention,amelioration, delay or reduction of severity and/or incidence of sideeffects associated with opioid administration, such as, for example,gastrointestinal dysfunction (e.g., inhibition of intestinal motility,constipation, GI sphincter constriction, nausea, emesis (vomiting),biliary spasm, opioid bowel dysfunction, colic), dysphoria, pruritus,urinary retention, depression of respiration, papillary constriction,cardiovascular effects, chest wall rigidity and cough suppression,depression of stress response, and immune suppression associated withadministration of narcotic analgesia, etc, or combinations thereof.Other uses of Compound 1, and forms thereof as described herein, are setforth infra.

Solid Forms of Compound 1:

It has been found that Compound 1 can exist in a variety of solid forms.Such forms include neat crystal forms, known as polymorphs. Such solidforms also include solvates, hydrates, and amorphous. All such solidforms of Compound 1 are contemplated by the present invention. Incertain embodiments, the present invention provides Compound 1 as amixture of one or more solid forms selected from polymorphs, solvates,hydrates, and amorphous Compound 1.

As used herein, the term “polymorph” refers to different crystalstructures achieved by a particular chemical entity. Specifically,polymorphs occur when a particular chemical compound can crystallizewith more than one structural arrangement. As used herein, the term“solvate” refers to a crystal form where a stoichiometric ornon-stoichiometric amount of solvent, or mixture of solvents, isincorporated into the crystal structure. Similarly, the term “hydrate”refers to a crystal form where a stoichiometric or non-stoichiometricamount of water is incorporated into the crystal structure.

In certain embodiments of the present invention, Compound 1 is providedas a crystalline solid. In some embodiments, the crystalline solid issubstantially free of amorphous Compound 1. As used herein, the term“substantially free of amorphous Compound 1” means that the solidcontains no significant amount of amorphous Compound 1. In certainembodiments of the present invention, the term “substantially free ofamorphous Compound 1” means that at least about 95% by weight ofCompound 1 in the solid is in crystalline form. In still otherembodiments of the invention, the term “substantially free of amorphousCompound 1” means that at least about 99% by weight of Compound 1 in thesolid is in crystalline form.

In certain embodiments of the present invention, Compound 1 is providedas a neat crystal form and thus does not have any water or solventincorporated into the crystal structure. It has been found that Compound1 can exist in at least one neat crystal form, or polymorph, referred toherein as Form A.

In certain embodiments, the present invention provides Form A ofCompound 1. In other embodiments, the present invention provides Form Aof Compound 1 characterized in that it has a peak in its X-ray powderdiffraction (“XRPD”) pattern at about 20.06 degrees 2-theta. As usedherein, the term “about”, when used in reference to any degree 2-thetavalue recited herein, refers to the stated value ±0.2 degree 2-theta.

In certain embodiments, degree 2-theta values, as described herein, arereported with two decimal places. In other embodiments, degree 2-thetavalues, as described herein, are reported with one decimal place. Instill other embodiments, degree 2-theta values, as described herein, arereported with no decimal places. It will be understood that where theterm “about” is used in reference to any degree 2-theta value recitedherein, this term refers to the stated value ±0.2 degree 2-theta inaccordance with the value's reported decimal place.

According to another embodiment, Form A of Compound 1 is characterizedin that it has one or more peaks in its calculated XRPD pattern, forsingle crystal data collected at a temperature of 150±1° K, selectedfrom those at about 13.6, 13.9, 16.85, 17.35, 23, 23.85, 24.7, 26.75,and 34.75 degrees 2-theta. In other embodiments, Form A of Compound 1 ischaracterized in that it has two or more, or three or more, peaks in itscalculated XRPD pattern, for single crystal data collected at atemperature of 150±1° K, selected from those at about 13.6, 13.9, 16.85,17.35, 23, 23.85, 24.7, 26.75, and 34.75 degrees 2-theta. In still otherembodiments, Form A of Compound 1 is characterized in that it hassubstantially all of the peaks in its calculated XRPD pattern, forsingle crystal data collected at a temperature of 150±1° K, selectedfrom those at about 13.6, 13.9, 16.85, 17.35, 23, 23.85, 24.7, 26.75,and 34.75 degrees 2-theta.

In other embodiments, Form A of Compound 1 is characterized in that ishas substantially all of the peaks in its XRPD pattern listed in Table1A, below.

TABLE 1A XRPD Peaks for Form A Form A (°2θ) 11.56 13.44 13.98 15.52 16.417.3 19.42 20.06 20.82 21.9 22.3 23.34 24.42 24.84 26.38 27 27.64 28.8229.16 29.7

In still other embodiments, Form A of Compound 1 is characterized inthat it has substantially all of the peaks in its XRPD pattern listed inTable 1B, below.

TABLE 1B XRPD Peaks for Form A Peak No. °2θ 1 9.42 2 11.56 3 13.44 413.98 5 15.52 6 16.4 7 17.3 8 17.78 9 19.42 10 20.06 11 20.82 12 21.9 1322.3 14 23.34 15 24.42 16 24.84 17 25.82 18 26.38 19 27 20 27.64 2128.62 22 29.16 23 29.7 24 30.04 25 30.5 26 31.1 27 31.5 28 32.28 2932.96 30 34.34 31 35.1 32 36 33 36.88 34 38.16 35 39.04 36 39.48

In certain embodiments of the present invention, Form A of Compound 1 ischaracterized in that it has substantially all of the peaks in its XRPDpattern, calculated from single crystal data collected at a temperatureof 150±1° K, listed in Table 1C, below.

TABLE 1C Calculated XRPD Peaks for a Single Crystal of Form A at 150 ±1° K Peak No. °2θ 1 9.5 2 11.35 3 11.75 4 13.3 5 13.6 6 13.9 7 15.3 816.85 9 17.35 10 17.95 11 19.5 12 20.3 13 20.65 14 21.15 15 21.8 1622.75 17 23 18 23.3 19 23.65 20 23.85 21 24.7 22 24.95 23 26.05 24 26.3525 26.75 26 27.2 27 28.35 28 29.25 29 29.65 30 30.1 31 31.1 32 31.25 3331.8 34 32.05 35 32.55 36 33.4 37 34.3 38 34.75

According to one aspect, Form A of Compound 1 has an XRPD patternsubstantially similar to that depicted in FIG. 1A. As used herein, thephrase “substantially all of the peaks” means that the compoundexhibits, in its XRPD, at least about 80% of the peaks listed. In otherembodiments, the phrase “substantially all of the peaks” means that thecompound exhibits, in its XRPD, at least about 85, 90, 95, 97, 98, or99% of the peaks listed. According to other embodiments, Form A ofCompound 1, has an XRPD pattern, calculated from single crystal datacollected at a temperature of 150±1° K, substantially similar to thatdepicted in FIG. 1B. In other embodiments, Form A is characterized inthat it has a DSC pattern substantially similar to that depicted in FIG.2.

In certain embodiments of the invention, Form A is characterized byrepresentative peaks in X-ray powder diffraction, which peaks aredetermined by comparison of X-ray diffraction pattern results forstandard preparations of Form B, Form C, and Form D. In someembodiments, Form A is characterized by representative peaks in X-raypowder diffraction, which peaks are within the range of about 1 to about30 degrees 2-theta, determined by comparison of X-ray diffractionpattern results for standard preparations of Form B, Form C, and Form D.Methods for preparing Form A of Compound 1 are described in the Examplessection, infra.

According to another embodiment, the present invention provides Compound1 as an amorphous solid. The X-ray powder diffraction pattern ofamorphous Compound 1 is depicted in FIG. 3. Amorphous solids are wellknown to one of ordinary skill in the art and are typically prepared bysuch methods as lyophilization, melting, and precipitation fromsupercritical fluid, among others. Methods of preparing amorphousCompound 1 are described in the Examples section, infra.

In certain embodiments, the present invention provides amorphousCompound 1 substantially free of crystalline Compound 1. As used herein,the term “substantially free of crystalline Compound 1” means that thecompound contains no significant amount of crystalline Compound 1.Crystalline Compound 1 includes neat crystal forms, solvates andhydrates as described herein or other crystalline forms of Compound 1that may result from the preparation of, and/or isolation of, amorphousCompound 1. In certain embodiments of the present invention, at leastabout 95% by weight of Compound 1 present is amorphous Compound 1. Instill other embodiments of the invention, at least about 99% by weightof Compound 1 present is amorphous Compound 1.

In other embodiments, the present invention provides a compositioncomprising amorphous Compound 1 and at least one crystalline form ofCompound 1. Such crystalline forms of Compound 1 include neat crystalforms, solvates and hydrates as described herein or other crystallineforms of Compound 1 that may result from the preparation of, and/orisolation of, amorphous Compound 1. In certain embodiments, the presentinvention provides a composition comprising amorphous Compound 1 and atleast one crystalline form of Compound 1 as described herein. In otherembodiments, the present invention provides a composition comprisingamorphous Compound 1 and at least one crystalline form of Compound 1selected from Form A, Form B, Form C, or Form D.

It has been found that Compound 1 can exist in at least two hydrateforms or mixed hydrate-solvate forms. Two such forms are referred toherein as Form B and Form D.

In certain embodiments, the present invention provides Form B ofCompound 1. In certain embodiments, the present invention provides FormB of Compound 1, substantially free of other forms of Compound 1. Inother embodiments, Form B is a mixed hydrate-methanolate of Compound 1.According to one embodiment, Form B is characterized in that it has oneor more peaks in its XRPD pattern selected from those at about 7.9,8.18, 20.3, 21.44, 24.11, and 25.12 degrees 2-theta. In certainembodiments, Form B is characterized in that it has two or more, orthree or more, peaks in its XRPD pattern selected from those at about7.9, 8.18, 20.3, 21.44, 24.11, and 25.12 degrees 2-theta. In otherembodiments, Form B is characterized in that it has substantially all ofthe peaks in its XRPD pattern selected from those at about 7.9, 8.18,20.3, 21.44, 24.11, and 25.12 degrees 2-theta.

In certain embodiments, Form B of Compound 1 is characterized in that ishas substantially all of the peaks in its XRPD pattern listed in Table2A, below.

TABLE 2A XRPD Peaks for Form B Form B (°2θ) 7.9 8.18 10.64 11.57 12.6813.44 13.89 14.38 15.42 16.01 16.39 17.18 19.89 20.79 21.44 21.9 23.3524.49 24.87 25.53 29.17

In still other embodiments, Form B of Compound 1 is characterized inthat is has substantially all of the peaks in its XRPD pattern listed inTable 2B, below.

TABLE 2B XRPD Peaks for Form B Peak No. °2θ 1 7.9 2 8.18 3 10.64 4 11.575 12.68 6 13.44 7 13.89 8 14.38 9 15.42 10 16.01 11 16.39 12 17.18 1317.74 14 18.12 15 18.47 16 19.37 17 19.89 18 20.3 19 20.79 20 21.44 2121.9 22 22.31 23 23.35 24 24.11 25 24.49 26 24.87 27 25.12 28 25.53 2926.33 30 26.78 31 27.51 32 28.1 33 29.17 34 29.69 35 30.07 36 30.76 3731.04 38 32.18 39 32.88 40 34.33

According to one aspect, Form B of Compound 1 has an XRPD patternsubstantially similar to that depicted in FIG. 4. In other embodiments,the present invention provides Form B of Compound 1 having a DSC patternsubstantially similar to that depicted in FIG. 5.

In certain embodiments of the invention, Form B is characterized byrepresentative peaks in X-ray powder diffraction, which peaks aredetermined by comparison of X-ray diffraction pattern results forstandard preparations of Form A, Form C, and Form D. In someembodiments, Form B is characterized by representative peaks in X-raypowder diffraction, which peaks are within the range of about 1 to about30 degrees 2-theta, determined by comparison of X-ray diffractionpattern results for standard preparations of Form A, Form C, and Form D.Methods for preparing Form B of Compound 1 are described in the Examplessection, infra.

In certain embodiments, the present invention provides Form D ofCompound 1. In other embodiments, the present invention provides Form Dof Compound 1, substantially free of other forms of Compound 1.According to one embodiment, Form D is characterized in that it has oneor more peaks in its XRPD pattern selected from those at about 7.66,8.42, 14.79, and 21.06 degrees 2-theta. In certain embodiments, Form Dis characterized in that it has two or more, or three or more, peaks inits XRPD pattern selected from those at about 7.66, 8.42, 14.79, and21.06 degrees 2-theta. In other embodiments, Form D is characterized inthat it has substantially all of the peaks in its XRPD pattern selectedfrom those at about 7.66, 8.42, 14.79, and 21.06 degrees 2-theta.

In certain embodiments, Form D of Compound 1 is characterized in that ishas substantially all of the peaks in its XRPD pattern listed in Table3A, below.

TABLE 3A XRPD Peaks for Form D Form D (°2θ) 7.66 8.42 12.85 13.48 16.1117.53 18.67 19.61 21.06 21.79 22.07 23.25 24.53 26.23

In still other embodiments, Form D of Compound 1 is characterized inthat is has substantially all of the peaks in its XRPD pattern listed inTable 3B, below.

TABLE 3B XRPD Peaks for Form D Peak No. °2θ 1 7.66 2 8.42 3 9.43 4 10.65 11.57 6 12.85 7 13.48 8 13.89 9 14.17 10 14.38 11 14.79 12 15.38 1316.11 14 17.22 15 17.53 16 18.67 17 19.61 18 20.79 19 21.06 20 21.79 2122.07 22 23.25 23 24.53 24 25.43 25 25.91 26 26.23 27 27.2 28 27.71 2928.06 30 28.55 31 29.03 32 29.86 33 30.56 34 31.11 35 32.22 36 32.7 3734.12 38 34.89 39 35.82 40 37 41 37.86 42 38.11 43 38.63 44 39.46

According to one aspect, Form D of Compound 1 has an XRPD patternsubstantially similar to that depicted in FIG. 6. In other embodiments,the present invention provides Form D of Compound 1 having a DSC patternsubstantially similar to that depicted in FIG. 7.

In certain embodiments of the invention, Form D is characterized byrepresentative peaks in X-ray powder diffraction, which peaks aredetermined by comparison of X-ray diffraction pattern results forstandard preparations of Form A, Form B, and Form C. In someembodiments, Form D is characterized by representative peaks in X-raypowder diffraction, which peaks are within the range of about 1 to about30 degrees 2-theta, determined by comparison of X-ray diffractionpattern results for standard preparations of Form A, Form B, and Form C.Methods for preparing Form D of Compound 1 are described in the Examplessection, infra.

It has been found that Compound 1 can exist in solvated crystallineforms. In certain embodiments, the present invention provides acrystalline n-propanolate of Compound 1, referred to herein as Form C.In certain embodiments, the present invention provides Form C ofCompound 1, substantially free of other forms of Compound 1. Accordingto another embodiment, Form C of Compound 1 is characterized in that ithas one or more peaks in its calculated XRPD pattern, for single crystaldata collected at a temperature of 150±1° K, selected from those atabout 10.8, 12.8, 14.8, 15.9, 16.25, 18.5, 19.15, 22, 23.6, 24.25, 25.7,27.5, 28.1, 28.9, 31.5, and 31.75 degrees 2-theta. In certainembodiments, Form C of Compound 1 is characterized in that it has two ormore, or three or more, peaks in its calculated XRPD pattern, for singlecrystal data collected at a temperature of 150±1° K, selected from thoseat about 10.8, 12.8, 14.8, 15.9, 16.25, 18.5, 19.15, 22, 23.6, 24.2.5,25.7, 27.5, 28.1, 28.9, 31.5, and 31.75 degrees 2-theta. In otherembodiments, Form C of Compound 1 is characterized in that it hassubstantially all of the peaks in its calculated XRPD pattern, forsingle crystal data collected at a temperature of 150±1° K, selectedfrom those at about 10.8, 12.8, 14.8, 15.9, 16.25, 18.5, 19.15, 22,23.6, 24.25, 25.7, 27.5, 28.1, 28.9, 31.5, and 31.75 degrees 2-theta.

In certain embodiments of the present invention, Form C of Compound 1 ischaracterized in that it has substantially all of the peaks in its XRPDpattern, calculated from single crystal data collected at a temperatureof 150±1° K, listed in Table 4A, below.

TABLE 4A XRPD Peaks Calculated for a Single Crystal of Form C at 150 ±1° K Peak No. °2θ 1 9.1 2 10.8 3 11.4 4 11.6 5 12.8 6 14.35 7 14.8 815.5 9 15.9 10 16.25 11 18.25 12 18.5 13 18.85 14 19.15 15 19.7 16 20.8517 21.2 18 21.65 19 21.85 20 22 21 22.65 22 22.95 23 23.3 24 23.6 2524.25 26 25.05 27 25.3 28 25.7 29 26 30 27.05 31 27.5 32 28.1 33 28.9 3429.5 35 29.9 36 30.45 37 30.75 38 31.5 39 31.75 40 32.15

In other embodiments, the present invention provides a compositioncomprising a mixture of Forms A and C of Compound 1. According toanother embodiment, the XRPD pattern of the mixture of Forms A and C(preferred orientation) of Compound 1 has one or both peaks at about10.58 and 22.74 degrees 2-theta. One of ordinary skill in the art willrecognize that the designation of “preferred orientation” refers to aphenomenon that occurs when crystals have a tendency to align during theprocess of collecting XRPD data. This phenomenon often results in theformation of larger peaks in the XRPD pattern, as would be recognized bya skilled practitioner. In certain embodiments of the present invention,the XRPD pattern of the mixture of Forms A and C (preferred orientation)of Compound 1 has substantially all of the peaks at about 10.58, 11.56,13.88, 15.42, 20.82, 21.86, 22.74, 23.2, 24.74, and 26.96 degrees2-theta.

In other embodiments, the XRPD pattern of the mixture of Forms A and C(preferred orientation) of Compound 1 has substantially all of the peaksin its XRPD pattern listed in Table 4B, below.

TABLE 4B XRPD Peaks for Forms A and C (preferred orientation) Peak No.°2θ 1 10.58 2 11.56 3 13.44 4 13.88 5 15.42 6 16.4 7 18.88 8 19.34 919.9 10 20.82 11 21.86 12 22.22 13 22.74 14 23.2 15 23.84 16 24.74 1725.7 18 26.96 19 28.7 20 29.14 21 29.64 22 34.02 23 34.66 24 35.08 2535.98 26 37.14 27 38.32 28 39.24

According to one aspect, Form C of Compound 1 has an XRPD pattern,calculated from single crystal data collected at a temperature of 150±1°K, substantially similar to that depicted in FIG. 8. According toanother aspect, a mixture of Forms A and C (preferred orientation) ofCompound 1 has an XRPD pattern substantially similar to that depicted inFIG. 9.

In certain embodiments of the invention, Form C is characterized byrepresentative peaks in X-ray powder diffraction, which peaks aredetermined by comparison of X-ray diffraction pattern results forstandard preparations of Form A, Form B, and Form D. In someembodiments, Form C is characterized by representative peaks in X-raypowder diffraction, which peaks are within the range of about 1 to about30 degrees 2-theta, determined by comparison of X-ray diffractionpattern results for standard preparations of Form A, Form B, and Form D.Methods for preparing Form C of Compound 1 are described in the Examplessection, infra.

In certain embodiments, the present invention provides Form A ofCompound 1 comprising one or more additional solid forms of Compound 1.In other embodiments, the present invention provides Form A of Compound1 comprising one or more of a hydrate of Compound 1, a solvate ofCompound 1, or amorphous compound 2. In still other embodiments, thepresent invention provides Form A of Compound 1 comprising one or moreof Form C, Form D, or amorphous, and optionally Form B. Thus, anotheraspect of the present invention provides a Compound 1 Composition.

As used herein, the term “Compound 1 Composition” refers to acomposition comprising at least two of Form A, Form C, Form D, andamorphous Compound 1, and optionally Form B. In other embodiments, theCompound 1 Composition comprises at least two of Form B, Form C, Form D,and amorphous Compound 1. In certain embodiments of the invention, theCompound 1 Composition comprises Form A of Compound 1 and Form D. Instill other embodiments, the Compound 1 Composition comprises Form A andamorphous Compound 1.

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides new forms of Compound1, which is useful as a peripheral mu opioid receptor antagonist andshows utility in clinically relevant models for treating opioid-inducedside effects. According to another aspect of the present invention,pharmaceutically acceptable compositions are provided, comprising aninventive form of Compound 1, or a Compound 1 Composition, as describedherein, and optionally comprising a pharmaceutically acceptable carrier,adjuvant, or vehicle. In certain embodiments of the present invention,such pharmaceutically acceptable compositions optionally furthercomprise one or more additional therapeutic agents.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with an inventive form ofCompound 1, or Compound 1 Composition, of the invention, such as byproducing any undesirable biological effect or otherwise interacting ina deleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, serum proteins,such as human serum albumin, buffer substances such as phosphates,glycine, sorbic acid, or potassium sorbate, partial glyceride mixturesof saturated vegetable fatty acids, water, salts or electrolytes, suchas protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt, gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

DEFINITIONS

As used herein, an “effective amount” of a compound or pharmaceuticallyacceptable composition can achieve a desired therapeutic and/orprophylactic effect. An “effective amount” is at least a minimal amountof a compound, or composition containing a compound, which is sufficientfor preventing, ameliorating, reducing, delaying, or diminishingseverity of one or more symptoms of a disorder associated withmodulation of peripheral μ opioid receptors, and/or for preventing,ameliorating, delaying or diminishing severity of side effectsassociated with opioid analgesic therapy (e.g., gastrointestinaldysfunction (e.g., dysmotility constipation, etc.), nausea, emesis,(e.g., nausea), etc.). An “effective amount” of a compound, orcomposition containing a compound, is sufficient for prevention,amelioration, reduction, delay or a decrease in the symptoms associatedwith, a disease associated with aberrant endogenous peripheral opioid orμ opioid receptor activity (e.g., idiopathic constipation, ileus, etc.).

The term “formulation” refers to a preparation that includes aninventive form of Compound 1, or Compound 1 Composition, in combinationwith one or more excipients for administration to a subject. In general,particular pharmaceutical additives are selected with the aim ofenabling an optimal release, distribution and development of activity ofan inventive form of Compound 1, or Compound 1 Composition, for therespective applications.

The term “subject”, as used herein, means a mammal and includes humanand animal subjects, such as domestic animals (e.g., horses, dogs, cats,etc.).

The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated.

An inventive form of Compound 1, or Compound 1 Composition, according tothe present invention, may be administered using any amount and anyroute of administration effective for treating or lessening the severityof a disorder associated with modulation of peripheral μ opioidreceptors. The exact amount required will vary from subject to subject,depending on the species, age, and general condition of the subject, theseverity of the infection, the particular agent, its mode ofadministration, and the like. It will be understood, however, that thetotal daily usage of an inventive form of Compound 1, or Compound 1Composition, will be decided by the attending physician within the scopeof sound medical judgment. The specific effective dose level for anyparticular patient or organism will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed, and like factors well known in the medical arts.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, nasally, rectally,parenterally, intracistemally, intravaginally, intraperitoneally,topically (as by powders, ointments, or drops), bucally, or the like,depending on the severity of the infection being treated. In certainembodiments, an inventive form of Compound 1, or Compound 1 Composition,may be administered orally or parenterally at dosage levels of about0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about25 mg/kg, of subject body weight per day, one or more times a day, toobtain the desired therapeutic effect.

Liquid dosage forms for oral or nasal administration include, but arenot limited to, pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, aerosols, gels, syrups, and elixirs. In additionto an inventive form of Compound 1, or Compound 1 Composition, theliquid dosage forms may contain inert diluents commonly used in the artsuch as, for example, water or other solvents, solubilizing agents andemulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents. Aerosol formulations typically comprise a solution or finesuspension of the active substance in a physiologically acceptableaqueous or non-aqueous solvent and are usually presented in single ormultidose quantities in sterile form in a sealed container, which cantake the form of a cartridge or refill for use with an atomising device.Alternatively the sealed container may be a unitary dispensing devicesuch as a single dose nasal inhaler or an aerosol dispenser fitted witha metering valve which is intended for disposal once the contents of thecontainer have been exhausted. Where the dosage form comprises anaerosol dispenser, it will contain a pharmaceutically acceptablepropellant. The aerosol dosage forms can also take the form of apump-atomiser.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

Advantageously, amorphous Compound 1, as described herein, has enhancedwater solubility. Accordingly, amorphous Compound 1 is useful forintravascular and intramuscular delivery. In certain embodiments, thepresent invention also relates to an injectable formulation forintravascular or intramuscular delivery.

In order to prolong the effect of an inventive form of Compound 1, orCompound 1 Composition, of the present invention, it is often desirableto slow the absorption of the compound from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Typical parenteral compositions consist of a solution or suspension ofthe compound in a sterile aqueous carrier or non-aqueous or parenterallyacceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone,lecithin, arachis oil or sesame oil. Alternatively, the solution can belyophilised and then reconstituted with a suitable solvent just prior toadministration.

Compositions for rectal or vaginal administration are conveniently inthe form of suppositories, pessaries, vaginal tabs, foams, or enemas.Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing an inventive form ofCompound 1, or Compound 1 Composition, with suitable non-irritatingexcipients or carriers such as cocoa butter, polyethylene glycol or asuppository wax which are solid at ambient temperature but liquid atbody temperature and therefore melt in the rectum or vaginal cavity andrelease the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, an inventiveform of Compound 1, or Compound 1 Composition, is mixed with at leastone inert, pharmaceutically acceptable excipient or carrier such assodium citrate or dicalcium phosphate and/or a) fillers or extenderssuch as starches, lactose, sucrose, glucose, mannitol, and silicic acid,b) binders such as, for example, carboxymethylcellulose, alginates,gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants suchas glycerol, d) disintegrating agents such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate, e) solution retarding agents such as paraffin, f)absorption accelerators such as quaternary ammonium salts, g) wettingagents such as, for example, cetyl alcohol and glycerol monostearate, h)absorbents such as kaolin and bentonite clay, and i) lubricants such astalk, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof. In the case of capsules,tablets and pills, the dosage form may also comprise buffering agents.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

An inventive form of Compound 1, or Compound 1 Composition, can also bein micro-encapsulated form with one or more excipients as noted above.The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings, release controlling coatings and other coatings well known inthe pharmaceutical formulating art. In such solid dosage forms aninventive form of Compound 1, or Compound 1 Composition, may be admixedwith at least one inert diluent such as sucrose, lactose or starch. Suchdosage forms may also comprise, as is normal practice, additionalsubstances other than inert diluents, e.g., tableting lubricants andother tableting aids such a magnesium stearate and microcrystallinecellulose. In the case of capsules, tablets and pills, the dosage formsmay also comprise buffering agents. They may optionally containopacifying agents and can also be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain part of theintestinal tract, optionally, in a delayed manner. Examples of embeddingcompositions that can be used include polymeric substances and waxes.

Compositions for oral administration may be designed to protect theactive ingredient against degradation as it passes through thealimentary tract, for example by an outer coating of the formulation ona tablet or capsule.

In another embodiment, an inventive form of Compound 1, or Compound 1Composition, is be provided in an extended (or “delayed” or “sustained”)release composition. This delayed release composition comprises aninventive form of Compound 1, or Compound 1 Composition, in combinationwith a delayed release component. This composition allows targetedrelease of an inventive form of Compound 1, or Compound 1 Composition,into the lower gastrointestinal tract; for example into the smallintestine, the large intestine, the colon and/or the rectum. In certainembodiments, the delayed release composition comprising an inventiveform of Compound 1, or Compound 1 Composition, further comprises anenteric or pH dependent coating such as cellulose acetate phthalates andother phthalates (e.g. polyvinyl acetate phthalate, methacrylates(Eudragits)). Alternatively, the delayed release composition providescontrolled release to the small intestine and/or colon by the provisionof pH sensitive methacrylate coatings, pH sensitive polymericmicrospheres, or polymers which undergo degradation by hydrolysis. Thedelayed release composition can be formulated with hydrophobic orgelling excipients or coatings. Colonic delivery can further be providedby coatings which are digested by bacterial enzymes such as amylose orpectin, by pH dependent polymers, by hydrogel plugs swelling with time(Pulsincap), by time dependent hydrogel coatings and/or by acrylic acidlinked to azoaromatic bonds coatings.

In certain embodiments, the delayed release compositions of the presentinvention comprise hypromellose, microcrystalline cellulose, and alubricant. The mixture of an inventive form of Compound 1, or Compound 1Composition, hypromellose and microcrystalline cellulose may beformulated into a tablet or capsule for oral administration. In certainembodiments, the mixture is granulated and pressed into tablets.

In other embodiments, the delayed release compositions of the presentinvention are provided in a mutltiparticulate formulation. A mixture ofan inventive form of Compound 1, or Compound 1 Composition, and asuitable polymer is granulated to form pellets which are coated. Incertain embodiments, the pellets are seal coated with a non-functionalcoating. In other embodiments, the pellets are first seal coated with anon-functional coating and then coated with a functional coating.

As used herein the term “non-functional coating” is a coating that doesnot effect the release rate of the drug. Examples of a non-functionalcoat include hydroxypropyl cellulose, hypromellose or polyvinyl alcohol.In certain embodiments, the non-functional coating is Opadry® Clear,which contains, hydroxypropyl methylcellulose and polyethylene glycol.

As used herein, the term “functional coating” is a coating that affectsthe release rate of the drug from the dosage form. Examples of afunctional coating include ethylcellulose and polymethacrylatederivatives (Eudragits).

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The compositions may contain from 0.1% to 99% (w/w) preferably from0.1-60% (w/w), more preferably 0.2-20% by weight and most preferably0.25 to 12% (w/w) of an inventive form of Compound 1, or Compound 1Composition, depending on the method of administration.

Combination Products and Combined Administration

In certain embodiments, an inventive form of Compound 1, or Compound 1Composition, may be administered alone to treat one or more disorders asdescribed herein, or alternatively may be administered in combinationwith (whether simultaneously or sequentially) one or more other activeagents useful to treat one or more disorders as described herein. Thus,an inventive composition, or formulation thereof, can be administeredconcurrently with, prior to, or subsequent to, one or more activeagents.

In certain embodiments, inventive compositions include one or more otheractive agents in addition to an inventive form of Compound 1, orCompound 1 Composition, that is not an inventive form of Compound 1, orCompound 1 Composition. In certain embodiments, the present inventionprovides a formulation that delivers an inventive form of Compound 1, orCompound 1 Composition, and at least one additional active agent.

In some embodiments, inventive formulations comprise both an opioid andan inventive form of Compound 1, or Compound 1 Composition. Suchcombination products, containing both an opioid and an inventive form ofCompound 1, or Compound 1 Composition, would allow simultaneous reliefof pain and minimization of opioid-associated side effects (e.g.,gastrointestinal effects (e.g., delayed gastric emptying, altered GItract motility), etc.).

Opioids useful in treatment of analgesia are known in the art. Forexample, opioid compounds include, but are not limited to, alfentanil,anileridine, asimadoline, bremazocine, burprenorphine, butorphanol,codeine, dezocine, diacetylmorphine (heroin), dihydrocodeine,diphenoxylate, ethylmorphine, fedotozine, fentanyl, funaltrexamine,hydrocodone, hydromorphone, levallorphan, levomethadyl acetate,levorphanol, loperamide, meperidine (pethidine), methadone, morphine,morphine-6-glucoronide, nalbuphine, nalorphine, nicomorphine, opium,oxycodone, oxymorphone, papaveretum, pentazocine, propiram,propoxyphene, remifentanyl, sufentanil, tilidine, trimebutine, andtramadol. In some embodiments the opioid is at least one opioid selectedfrom alfentanil, buprenorphine, butorphanol, codeine, dezocine,dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol,meperidine (pethidine), methadone, morphine, nalbuphine, nicomorphine,oxycodone, oxymorphone, papaveretum, pentazocine, propiram,propoxyphene, sufentanil and/or tramadol. In certain embodiments of thepresent invention, the opioid is selected from morphine, codeine,oxycodone, hydrocodone, dihydrocodeine, propoxyphene, fentanyl,tramadol, and mixtures thereof. In a particular embodiment, the opioidis loperamide. In other embodiments, the opioid is a mixed agonist suchas butorphanol. In some embodiments, the subjects are administered morethan one opioid, for example, morphine and heroin or methadone andheroin.

The amount of additional active agent(s) present in combinationcompositions of this invention will typically be no more than the amountthat would normally be administered in a composition comprising thatactive agent as the only therapeutic agent. In certain embodiments ofthe present invention, the amount of additional active agent will rangefrom about 50% to 100% of the amount normally present in a compositioncomprising that compound as the only therapeutic agent.

In certain embodiments, inventive formulations may also be used inconjunction with and/or in combination with conventional therapies forgastrointestinal dysfunction to aid in the amelioration of constipationand bowel dysfunction. For example, conventional therapies include, butmay not be limited to functional stimulation of the intestinal tract,stool softening agents, laxatives (e.g., diphelymethane laxatives,cathartic laxatives, osmotic laxatives, saline laxatives, etc), bulkforming agents and laxatives, lubricants, intravenous hydration, andnasogastric decompression.

Uses and Kits of Inventive Formulations

As discussed above, the present invention provides inventive forms ofCompound 1, or Compound 1 Compositions, and pharmaceutically acceptablecompositions and formulations thereof, useful in antagonizingundesirable side effects of opioid analgesic therapy (e.g.,gastrointestinal effects (e.g., delayed gastric emptying, altered GItract motility), etc.). Furthermore, inventive forms of Compound 1, or aCompound 1 Composition, and pharmaceutically acceptable compositions andformulations thereof, may be used as to treat subjects having diseasestates that are ameliorated by binding μ opioid receptors, or in anytreatment wherein temporary suppression of the μ opioid receptor systemis desired (e.g., ileus, etc.). In certain embodiments of the presentinvention, methods of use of formulations are in human subjects.

Accordingly, administration of an inventive form of Compound 1, or aCompound 1 Composition, or a pharmaceutically acceptable composition orformulation thereof, may be advantageous for treatment, prevention,amelioration, delay or reduction of side effects of opioid use, such as,for example, gastrointestinal dysfunction (e.g., inhibition ofintestinal motility, constipation, GI sphincter constriction, nausea,emesis (vomiting), biliary spasm, opioid bowel dysfunction, colic,dysphoria, pruritus, urinary retention, depression of respiration,papillary constriction, cardiovascular effects, chest wall rigidity andcough suppression, depression of stress response, and immune suppressionassociated with use of narcotic analgesia, etc, or combinations thereof.Use of an inventive form of Compound 1, or a Compound 1 Composition, ora pharmaceutically acceptable composition or formulation thereof, maythus be beneficial from a quality of life standpoint for subjectsreceiving opioids, as well as to reduce complications arising fromchronic constipation, such as hemorrhoids, appetite suppression, mucosalbreakdown, sepsis, colon cancer risk, and myocardial infarction.

In some embodiments, inventive forms of Compound 1, or Compound 1Compositions, and pharmaceutically acceptable compositions andformulations thereof, are useful for administration to a subjectreceiving acute opioid administration. In some embodiments, providedformulations are useful for administration to patients suffering frompost-operative gastrointestinal dysfunction.

In other embodiments, inventive forms of Compound 1, or Compound 1Compositions, and pharmaceutically acceptable compositions andformulations thereof, are also useful for administration to subjectsreceiving chronic opioid administration (e.g., terminally ill patientsreceiving opioid therapy such as an AIDS patient, a cancer patient, acardiovascular patient; subjects receiving chronic opioid therapy forpain management; subjects receiving opioid therapy for maintenance ofopioid withdrawal). In some embodiments, the subject is a subject usingopioid for chronic pain management. In some embodiments, the subject isa terminally ill patient. In other embodiments the subject is a personreceiving opioid withdrawal maintenance therapy.

Alternative or additional uses for inventive forms of Compound 1, orCompound 1 Compositions, and pharmaceutically acceptable compositionsand formulations thereof, described herein may be to treat, reduce,inhibit, or prevent effects of opioid use including, e.g., aberrantmigration or proliferation of endothelial cells (e.g., vascularendothelial cells), increased angiogenesis, and increase in lethalfactor production from opportunistic infectious agents (e.g.,Pseudomonas aeruginosa). Additional advantageous uses of inventive formsof Compound 1, or Compound 1 Compositions, and pharmaceuticallyacceptable compositions and formulations thereof, include treatment ofopioid-induced immune suppression, inhibition of angiogenesis,inhibition of vascular proliferation, treatment of pain, treatment ofinflammatory conditions such as inflammatory bowel syndrome, treatmentof infectious diseases and diseases of the musculoskeletal system suchas osteoporosis, arthritis, osteitis, periostitis, myopathies, andtreatment of autoimmune diseases.

In certain embodiments, inventive forms of Compound 1, or Compound 1Compositions, and pharmaceutically acceptable compositions andformulations thereof, of the invention may be used in methods forpreventing, inhibiting, reducing, delaying, diminishing or treatinggastrointestinal dysfunction, including, but not limited to, irritablebowel syndrome, opioid-induced bowel dysfunction, colitis,post-operative or postpartum ileus, nausea and/or vomiting, decreasedgastric motility and emptying, inhibition of the stomach, and smalland/or large intestinal propulsion, increased amplitude ofnon-propulsive segmental contractions, constriction of sphincter ofOddi, increased anal sphincter tone, impaired reflex relaxation withrectal distention, diminished gastric, biliary, pancreatic or intestinalsecretions, increased absorption of water from bowel contents,gastro-esophageal reflux, gastroparesis, cramping, bloating, abdominalor epigastric pain and discomfort, constipation, idiopathicconstipation, post-operative gastrointestinal dysfunction followingabdominal surgery (e.g., colectomy (e.g., right hemicolectomy, lefthemicolectomy, transverse hemicolectomy, colectomy takedown, lowanterior resection)), and delayed absorption of orally administeredmedications or nutritive substances.

Provided forms of Compound 1, or Compound 1 Compositions, andpharmaceutically acceptable compositions and formulations thereof, arealso useful in treatment of conditions including cancers involvingangiogenesis, immune suppression, sickle cell anemia, vascular wounds,and retinopathy, treatment of inflammation associated disorders (e.g.,irritable bowel syndrome), immune suppression, chronic inflammation.

In still further embodiments, veterinary applications (e.g., treatmentof domestic animals, e.g. horse, dogs, cats, etc.) of use of inventiveforms of Compound 1, or Compound 1 Compositions, and pharmaceuticallyacceptable compositions and formulations thereof, are provided. Thus,use of provided, formulations in veterinary applications analogous tothose discussed above for human subjects is contemplated. For example,inhibition of equine gastrointestinal motility, such as colic andconstipation, may be fatal to a horse. Resulting pain suffered by thehorse with colic can result in a death-inducing shock, while a long-termcase of constipation may also cause a horse's death. Treatment ofequines with peripheral opioid receptor antagonists has been described,e.g., in U.S. Patent Publication No. 20050124657 published Jan. 20,2005.

It will also be appreciated that inventive forms of Compound 1, orCompound 1 Compositions, and pharmaceutically acceptable compositionsand formulations thereof, can be employed in combination therapies, thatis, inventive forms of Compound 1, or Compound 1 Compositions, andpharmaceutically acceptable compositions and formulations thereof, canbe administered concurrently with, prior to, or subsequent to, one ormore other desired therapeutics or medical procedures. Particularcombination therapies (therapeutics or procedures) to employ in acombination regimen will take into account compatibility of the desiredtherapeutics and/or procedures and the desired therapeutic effect to beachieved. It will also be appreciated that therapies employed mayachieve a desired effect for the same disorder (for example, aformulation may be administered concurrently with another compound usedto treat the same disorder), or they may achieve different effects(e.g., control of any adverse effects). As used herein, additionaltherapeutic compounds which are normally administered to treat orprevent a particular disease, or condition, are known as “appropriatefor the disease, or condition, being treated”.

In other embodiments, inventive forms of Compound 1, or Compound 1Compositions, and pharmaceutically acceptable compositions andformulations thereof, and unit dose forms are useful in preparation ofmedicaments, including, but not limited to medicaments useful in thetreatment of side effects of opioid use (e.g., gastrointestinal sideeffects (e.g., inhibition of intestinal motility, GI sphincterconstriction, constipation) nausea, emesis, (vomiting), dysphoria,pruritus, etc.) or a combination thereof. Inventive forms of Compound 1,or Compound 1 Compositions, and pharmaceutically acceptable compositionsand formulations thereof, are useful for preparations of medicaments,useful in treatment of patients receiving acute opioid therapy (e.g.,patients suffering from post-operative gastrointestinal dysfunctionreceiving acute opioid administration) or subjects using opioidschronically (e.g., terminally ill patients receiving opioid therapy suchas an AIDS patient, a cancer patient, a cardiovascular patient; subjectsreceiving chronic opioid therapy for pain management; or subjectsreceiving opioid therapy for maintenance of opioid withdrawal). Stillfurther, preparation of medicaments useful in the treatment of pain,treatment of inflammatory conditions such as inflammatory bowelsyndrome, treatment of infectious diseases, treatment of diseases of themusculoskeletal system such as osteoporosis, arthritis, osteitis,periostitis, myopathies, treatment of autoimmune diseases and immunesuppression, therapy of post-operative gastrointestinal dysfunctionfollowing abdominal surgery (e.g., colectomy (e.g., right hemicolectomy,left hemicolectomy, transverse hemicolectomy, colectomy takedown, lowanterior resection), idiopathic constipation, and ileus (e.g.,post-operative ileus, post-partum ileus), and treatment of disorderssuch as cancers involving angiogenesis, chronic inflammation and/orchronic pain, sickle cell anemia, vascular wounds, and retinopathy.

Still further encompassed by the invention are pharmaceutical packsand/or kits comprising an inventive form of Compound 1, or Compound 1Composition, or a pharmaceutically acceptable composition or formulationthereof, and a container (e.g., a foil or plastic package, or othersuitable container). Optionally instructions for use are additionallyprovided in such kits.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

All features of each of the aspects of the invention apply to all otheraspects mutatis mutandis.

EXEMPLIFICATION General Procedures

Compound 1 is prepared according to the methods described in detail inInternational Patent Application publication number WO2006/127899, theentirety of which is hereby incorporated herein by reference.

X-Ray Powder Diffraction (XRPD):

X-ray powder diffraction (XRPD) analyses were performed using a ShimadzuXRD-6000 X-ray powder diffractometer using Cu Kα radiation. Theinstrument is equipped with a long fine focus X-ray tube. The tubevoltage and amperage were set to 40 kV and 40 mA, respectively. Thedivergence and scattering slits were set at 1° and the receiving slitwas set at 0.15 mm. Diffracted radiation was detected by a NaIscintillation detector. A 0-20 continuous scan at 3°/min (0.4 sec/0.02°step) from 2.5 to 40° 2θ was used. A silicon standard was analyzed tocheck the instrument alignment. Data were collected and analyzed usingXRD-6100/7000 v. 5.0. Samples were prepared for analysis by placing themin an aluminum holder with silicon insert.

XRPD Pattern Analyses: X-ray powder diffraction (XRPD) analyses wereperformed using an Inel XRG-3000 diffractometer equipped with a CPS(Curved Position Sensitive) detector with a 20 range of 1200. Real timedata were collected using Cu-Kα radiation at a resolution of 0.03° 2θ.The tube voltage and amperage were set to 40 kV and 30 mA, respectively.The monochromator slit was set at 5 mm by 160 μm or at 2 mm by 160 μm.The pattern is displayed from 2.5-40° 2θ. Samples were prepared foranalysis by packing them into thin-walled glass capillaries. Eachcapillary was mounted onto a goniometer head that is motorized to permitspinning of the capillary during data acquisition. The samples wereanalyzed for 5 min or 10 min. Instrument calibration was performed usinga silicon reference standard.

XRPD Pattern Collection:

XRPD patterns were collected with a Bruker D-8 Discover diffractometerand Bruker's General Area Diffraction Detection System (GADDS, v.4.1.20). An incident beam of Cu Kα radiation was produced using afine-focus tube (40 kV, 40 mA), a Göbel mirror, and a 0.5 mmdouble-pinhole collimator. A specimen of the sample was packed in acapillary and secured to a translation stage. A video camera and laserwere used to position the area of interest to intersect the incidentbeam in transmission geometry. The incident beam was scanned to optimizeorientation statistics. A beam-stop was used to minimize air scatterfrom the incident beam at low angles. Diffraction patterns werecollected using a Hi-Star area detector located 15 cm from the sampleand processed using GADDS. The intensity in the GADDS image of thediffraction pattern was integrated using a step size of 0.04° 2θ. Theintegrated patterns display diffraction intensity as a function of 2θ.Prior to the analysis a silicon standard was analyzed to verify the Si111 peak position. XRPD peak listings were generated using Pattern Matchsoftware, version 2.1.1.

Differential Scanning Calorimetry (“DSC”):

Differential scanning calorimetry was performed using a TA Instrumentsdifferential scanning calorimeter 2920. The sample was placed into analuminum DSC pan, and the weight accurately recorded. The pan wascovered with a lid and left uncrimped. The sample cell was heated undera nitrogen purge at a rate of 10° C./min, up to a final temperature of250 or 300° C. Indium metal was used as the calibration standardReported temperatures are at the Transition maxima.

Thermogravimetry (“TG”):

Thermogravimetric analyses were performed using a TA Instruments 2950thermogravimetric analyzer. Each sample was placed in an aluminum samplepan and inserted into the TG furnace. The furnace was heated undernitrogen at a rate of 10° C./min, up to a final temperature of 350° C.Nickel and AlumelÔ were used as the calibration standards.

Solution ID ¹H NMR Spectroscopy: The solution ¹H NMR spectra wereacquired at ambient temperature with a Varian ^(UNITY)INOVA-400spectrometer at a ¹H Larmor frequency of 399.796 MHz. The sample wasdissolved in DMSO-d₆. The spectrum was acquired with a ¹H pulse width of8.2 μs, a 2.50 second acquisition time, a 5 second delay between scans,a spectral width of 6400 Hz with 32000 data points, and 40 co-addedscans. The free induction decay (FID) was processed using Varian VNMR6.1C software with 131072 points and an exponential line broadeningfactor of 0.2 Hz to improve the signal-to-noise ratio.

The residual peak from incompletely deuterated DMSO is at approximately2.50 ppm. The relatively broad peak at approximately 3.3 ppm is due towater. The spectrum was referenced to internal tetramethylsilane (TMS)at 0.0 ppm.

Example 1 Preparation of Form A

Compound 1 (54.7 mg) was dissolved in 2,2,2-trifluoroethanol (2 mL), andthe solution was filtered through a 0.2 μm nylon filter into a 20-mLvial. The 20-mL vial was placed inside a 100-mL glass jar containing 5mL of ethyl acetate. The 20-mL vial was left uncapped and the jar wascapped to allow vapor diffusion to occur. After four days, singlecrystals were observed in solution.

The monoclinic cell parameters and calculated volume at 150° K are:a=7.9013(3)Å, b=12.7337(9)Å, c=9.4247(7)Å, α=90.00°, β=98.868(4)°,γ=90.00°, V=936.91(10) Å³, wherein each value is ±1.5. For Compound 1,Form A, the formula weight is 435.35 g/mol with Z=2 resulting in acalculated density is 1.543 g cm⁻³. The space group was determined to beP21 (no. 4), this is a chiral space group. A single crystal of Form A ofCompound 1 was indexed at room temperature and the unit cell parametersare summarized in Table 5, below.

TABLE 5 Unit Cell Data for Form A Form A Form A 150° K Data RT Dataspace group P2₁ (No. 4) P2₁ (No. 4) a, Å 7.9013(3) 7.752(2) b, Å12.7337(9) 13.038(12) c, Å 9.4247(7) 9.493(3) α, deg 90 90 β, deg98.868(4) 97.98(2) γ, deg 90 90 V, Å³ 936.19(10) 945.7 Z 2 2 temp K 150298

Example 2 Preparation of Form B

Compound 1 (52.8 mg) was dissolved in methanol (35 mL) with sonicationto obtain a clear solution. The solution was filtered through a 0.2 μmnylon filter (Whatman) and evaporated using a rotary evaporator (ambienttemperature bath used). The sample was left on the rotary evaporator forapproximately 1 hour after the sample was visually dry. White solidcontaining birefringent spherulites of needles and blades resulted. AnXRPD pattern of Form A+peaks was observed when the evaporation wascarried out at approx. 45° C.

Example 3 Preparation of Form C

Compound 1 (321.5 mg) was dissolved in TFE (4.28 mL) with sonication. Aclear solution resulted. The solution was filtered through a 0.2 μmnylon filler (Whatman) into a clean 20-mL vial. A 500 μL aliquot of thefiltered solution was dispensed into a 1-dram vial. Into this vial,aliquots (500 μL) of 1-propanol were dispensed with stirring until atotal of 3 mL had been added. A clear solution resulted. The solutionwas allowed to stand at ambient conditions for approximately 1 hour. Thesample was found to contain a very small amount of white precipitatesuspended in solution. It was then placed in a refrigerator. A clearsolution containing colorless specks of solid resulted after 5 days. Thesolution was drawn off with a pipette and discarded, and the solid wasallowed to air dry at ambient conditions overnight. The samplecontaining birefringent pentagonal plates was submitted for singlecrystal X-ray analysis.

The monoclinic cell parameters and calculated volume are: a=7.7724(6) Å,b=15.2539(6) Å, c=9.7329(6) Å, α=90.00°, β=91.899(3)°, γ=90.00°,V=153.29(12) Å³, wherein each value is ±1.5. For Compound 1 the formulaweight is 496.45 g/mol with Z=2 the resulting calculated density of thecrystal structure is 1.430 g cm⁻³. The space group was determined to beP21 (no. 4), this is a chiral space group. The unit cell parameters forForm C are summarized in Table 6, below.

TABLE 6 Unit Cell Data for Form C Form C 150° K Data space group P2₁(No. 4) a, Å 7.7724(6) b, Å 15.2539(6) c, Å 9.7329(6) b, deg 91.899(3)V, Å³ 1153.29(12) Z 2 crystal dimensions, mm 0.50 × 0.48 × 0.25 temp K150

Example 4 Preparation of Form D

Amorphous Compound 1 was dissolved in methanol (concentrationapproximately 5 mg/mL) with sonication. A clear solution resulted. Thesolution was filtered through a 0.2 μm nylon filter (Whatman). Fastaddition of ethyl acetate to a ratio of 4:1 ethyl acetate:methanolcaused Form D to precipitate. The resulting white solid appeared to benon-birefringent and of unknown morphology. Experiments in which ethylacetate was added more slowly to the same solvent ratio resulted in aclear solution. Slow evaporation of the solution resulted in white solidcontaining birefringent spherulites of thin needles. A fast evaporationexperiment in which toluene replaced ethyl acetate also resulted inwhite solid containing large birefringent needles.

Example 5 Preparation of Amorphous Compound 1

Amorphous Compound 1 was prepared by lyophilization from an aqueoussolution. A cycling DSC experiment was carried out on the amorphousCompound 1 and the glass transition temperature was determined to beapproximately 23° C.

Example 6 Polymorph Screening of Compound 1

The forms of Compound 1, as described herein, were identified by apolymorph screen. In this screen, Compound 1 was subjected to a varietyof solvents and conditions to effect crystallization or precipitation.The results of this screen are summarized in Tables 7 though 13, below.These Tables indicate the solvent and conditions utilized, the formobtained (as determined by XRPD), and a description of the crystalhabit. In these Tables, the conditions are designated as slurry, FE, SC,FD, CP, RE, or SE. Each of these terms is defined in detail below.

As used herein, the term “Crash Precipitation” (“CP”) refers to a methodwhere saturated solutions of Compound 1 were prepared in varioussolvents and filtered through a 0.2-μm nylon filter into an open vial.Aliquots of various antisolvents were dispensed with stirring untilprecipitation occurred. In some cases, samples were placed in therefrigerator or freezer to facilitate precipitation. Solids werecollected by drawing solvent off with a pipette and allowing the solidsto air dry at ambient conditions prior to analysis.

As used herein, the term “Freeze Drying” (“FD”) refers to a method wherea saturated solution of Compound 1 was prepared in water and thesolution was filtered through a 0.2-μm nylon filter into an open vial.The solution was frozen in a thin layer on the walls of the vial byrotating in a bath of liquid nitrogen or dry ice and washingisopropanol. The vial containing the frozen sample was placed into alyophilizing container which was then attached to a Flexi-Drylyophilizer for one to three days. The temperature was maintained at −50to −60° C. for the duration of the experiment.

The term “Fast Evaporation” (“FE”) refers to a method where solutions ofCompound 1 were prepared in various solvents in which samples weresonicated between aliquot additions. Once a mixture reached completedissolution, as judged by visual observation, the solution was filteredthrough a 0.2-μm nylon filter. The filtered solution was allowed toevaporate at ambient conditions in an open vial. The solids wereisolated and analyzed.

The term “Rotary Evaporation” (“RE”) refers to a method whereconcentrated solutions of Compound 1 or amorphous Compound 1 wereprepared in various organic solvents and filtered through a 0.2-μm nylonfilter into an open vial or flask. In some cases, 4-5 mL aliquots of thefiltered solution were dispensed into a clean vial. The vial wasattached to a rotary evaporator and the solvent was evaporated todryness. The water bath was at ambient temperature usually, but in somecases, the water bath was heated to approximately 50° C. to facilitateevaporation. If the sample was not completely dry after rotaryevaporation, the vial was placed in a vacuum oven at 25° C. for 18hours. The solids were isolated and analyzed.

As used herein, the term “Slow Cool” (“SC”) refers to a method wheresaturated solutions of Compound 1 were prepared in various solvents atan elevated temperature and filtered warm through a 0.2-μm nylon filterinto a warm vial. The vial was capped and left on the hot plate, and thehot plate was turned off to allow the sample to slow cool to ambienttemperature.

The term “Slow Evaporation” (“SE”) refers to a method where solutions ofCompound 1 were prepared in various solvents in which samples weresonicated between aliquot additions. Once a mixture reached completedissolution, as judged by visual observation, the solution was filteredthrough a 0.2-μm nylon filter. In some cases, aliquots of antisolventwere then added to the filtered solution with stirring. The solution wasallowed to evaporate at ambient conditions in a vial covered withaluminum foil perforated with pinholes. The solids were isolated andanalyzed.

The term “Slurry Experiments” refers to a method where suspensions ofCompound 1 were prepared by adding enough solids to a given solvent atambient conditions or elevated temperature so that undissolved solidswere present. The mixture was then loaded onto an orbit shaker in ascaled vial at either ambient or elevated temperature for 7 days. Thesolids were isolated by vacuum filtration or by drawing the liquid phaseoff with a pipette and allowing the solids to air dry at ambientconditions prior to analysis.

As used herein, the term “Vapor Diffusion Experiments” refers to amethod where concentrated solutions of Compound 1 were prepared invarious solvents and filtered through a 0.2-μm nylon filter. Thefiltered solution was dispensed into a 1-dram vial, which was thenplaced inside a 20-mL vial containing approximately 2 mL of antisolvent.The 1-dram vial was left uncapped and the 20-mL vial was capped to allowvapor diffusion to occur. Solids were collected by vacuum filtration andanalyzed.

The term “Capillary Crystallization Techniques” refers to a method wherea capillary polymorph screen was carried out on Compound 1. Variouscrystallization techniques were employed. These techniques are describedbelow. X-ray powder diffraction quality capillaries were used. Oncesolids were observed from the crystallization attempts, they wereexamined under a microscope for birefringence and morphology. Anycrystalline shape was noted, but sometimes the solid exhibited unknownmorphology, in some cases due to the packing in the capillary or tosmall particle size. When sufficient, solid samples were then analyzedby XRPD, and the crystalline patterns were compared to each other toidentify new crystalline forms.

The term “CentriVap Crystallizations” (“CentriVap”) refers to a methodwhere a solution of Compound 1 in a given solvent or solvent mixture wasprepared and filtered through a 0.2-μm nylon filter. A capillary wasfilled with 45 μL of solution via syringe. The capillary wascentrifuged. The solvent was evaporated in a Labconco CentriVap®centrifugal evaporator under reduced pressure using a mechanical vacuumpump. The evaporator temperature was maintained at ambient temperature.

The term “Evaporation in Capillary” (“EC”) refers to a method where asolution of Compound 1 in a given solvent or solvent mixture wasprepared and filtered through a 0.2-μm nylon filter. A capillary wasfilled with 45 μL of solution via syringe. The capillary wascentrifuged. Evaporations were performed in open capillaries at ambientand elevated temperature.

The term “Solvent/Antisolvent Crystallizations in Capillary” refers to amethod where a solution of Compound 1 in a given solvent was preparedand filtered through a 0.2-μm nylon filter. A capillary was filled with15 μL of solution and centrifuged. Then 30 μL, of an antisolvent wasadded. The capillary was centrifuged. If a clear solution resulted, thecapillary was left at ambient conditions to allow the solvents toevaporate, or evaporation was performed in a Labconco Centrivapcentrifugal evaporator under reduced pressure using a mechanical pump atambient conditions.

The term “Vapor Diffusion in Solid or Vapor Stress” (“VS”) refers to amethod where capillaries were packed with approximately 1 cm ofCompound 1. The solids were exposed to solvent vapors by placing thecapillaries in tall vials containing about 5 mL of various solvents. Thecapillaries were removed after approximately 14 days.

TABLE 7 Polymorph Screen of Compound 1 XRPD Solvent ConditionsHabit/Description Result acetone slurry, 7 days tiny white plates, Aair-dried, 1 day birefringent acetonitrile slurry, 7 days white,morphology A air-dried, 1 day unknown, birefringent 2-butanone slurry, 7days white, morphology A air-dried, 1 day unknown, birefringent t-butylmethyl slurry, 7 days white blades, A ether air-dried, 3 daysbirefringent methylene slurry, 7 days white, morphology A chlorideair-dried, 1 day unknown, birefringent diisopropyl slurry, 7 days white,morphology A ether air-dried, 1 day unknown, birefringent 1,4-dioxaneslurry, 7 days white plates, A air-dried, 3 days birefringent ethanolslurry, 4 days clear solution — FE, orange glassy film, not amorphousair-dried, 3 days birefringent; morphology unknown, birefringent SCclear yellow solution — SE clear yellow solution — RE yellow glassyfilm, not amorphous birefringent; yellow, morphology unknown,birefringent ethyl acetate slurry, 7 days white plates and blades, Aair-dried, 3 days birefringent heptane slurry, 7 days white, morphologyA air-dried, 3 days unknown, birefringent hexafluoro- FE clear glassyfilm, not — isopropanol birefringent SE clear glassy film, not —birefringent CP w/ white, morphology A acetonitrile unknown,birefringent CP w/ white, morphology A 2-butanone unknown, birefringentCP w/ white spherulites of A isopropyl ether needles and morphologyunknown, birefringent CP w/ orange plates and A minus one 1,4-dioxanemorphology unknown, peak birefringent; morphology unknown, notbirefringent CP w/ tiny white spherulites of A ethyl acetate blades,birefringent CP w/ white, morphology amorphous isopropanol unknown,birefringent CP w/ white blades, A n-propanol birefringent RE white,bubbly solid amorphous isopropanol slurry, 7 days white plates andblades, A birefringent methanol FE tiny white blades, A birefringent SEamber-colored oily film, A not birefringent; plates and morphologyunknown, birefringent SC clear solution — RE white spherulites of Bneedles, birefringent RE (scale up) white spherulites of B needles andblades, birefringent white, morphology B unknown, partiallybirefringent; fibers, birefringent RE at white, morphology A + peaks 45°C. to ambient unknown, partially birefringent nitromethane slurry, 7days white, morphology A air-dried, 3 days unknown, birefringent FEamber-colored, large A (liquid phase pentagonal plates, from slurrybirefringent 2454-01-12) nitromethane: SE white cracked glass, Ahexafluoro- birefringent isopropanol 10:1 nitromethane: SE white platesand A 2,2,2- dendridic needles, trifluoroethanol birefringent 6:11-propanol slurry, 7 days white, morphology A air-dried, 3 days unknown,birefringent tetrahydrofuran slurry, 7 days white plates and blades, Aair-dried, 3 days birefringent toluene slurry, 7 days white plates andblades A air-dried, 3 days toluene: SE textured glassy film, Ahexafluoro- not birefringent; off- isopropanol white, morphology 10:1unknown, not birefringent; off-white needles, birefringent toluene:2,2,2- SE yellow translucent — trifluoroethanol glassy film, not 6:1birefringent 2,2,2- FE clear glassy film, not — trifluoroethanolbirefringent SE clear textured glassy — film, not birefringent CP w/white plates, A acetonitrile birefringent CP w/ white blades, A2-butanone birefringent CP w/ white, morphology A 1,4-dioxane unknown,birefringent CP w/ white, morphology A ethyl acetate unknown, notbirefringent CP w/ white needles and A isopropanol blades, birefringentCP w/ white, pentagonal A + C n-propanol plates, birefringent RE white,bubbly solid; amorphous dendridic needles, birefringent water FE yellowglassy film, not — birefringent SE light yellow glassy — film, notbirefringent acetone:water FE clear glassy film, not — 50:50birefringent SE clear glassy film, not — birefringent acetone:waterslurry, 7 days white plates and blades, A 99:1 birefringentacetonitrile: FE clear glassy film, not amorphous water 80:20birefringent; colorless, morphology unknown, birefringent SE clearglassy film, not amorphous birefringent; colorless, morphology unknown,birefringent acetonitrile: slurry, 7 days white plates and blades, Awater 99:1 birefringent isopropanol: FE clear glassy film, not — water50:50 birefringent SE off-white, morphology A unknown, birefringentisopropanol: slurry, 7 days tiny white plates, A water 99:1 birefringentacetone slurry, 7 days white, morphology A unknown, birefringentacetonitrile slurry, 7 days white, morphology A unknown, birefringent FEcolorless textured — (liquid phase glassy film, not from slurrybirefringent 2454-20-02) tetrahydrofuran slurry, 7 days white,morphology A unknown, birefringent

TABLE 8 Vapor Diffusion Experiments XRPD Solvent Antisolvent TimeHabit/Description Result hexafluoro- acetone  6 days white, morphology Aisopropanol unknown, birefringent dichloro- 14 days clear solution —methane 2,2,2- acetone 10 days translucent, morphology A trifluoro-unknown, not ethanol birefringent; white plates, birefringent dichloro-14 days clear solution — methane

TABLE 9 Capillary Polymorph Screen of Compound 1 XRPD Solvent MethodHabit/Description Result hexafluoro- EC, ambient clear solution —isopropanol EC, 40° C. clear glassy solid, not — birefringent CentriVapoff-white solid, glassy, — not birefringent and viscous liquid 2,2,2-EC, ambient off-white dendridic IS trifluoro- formations, ethanolbirefringent EC, 40° C. clear yellow glassy — solid, not birefringentCentriVap off-white, morphology A unknown, birefringent water EC,ambient clear yellowish — solution EC, 40° C. clear yellow viscous —liquid CentriVap clear glassy, not — birefringent acetone: EC, ambientclear yellowish — water 50:50 solution EC, 40° C. clear yellowish sticky— substance CentriVap off-white, morphology A (small unknown,birefringent amount of material acetonitrile: EC, ambient yellowishviscous — water 50:50 liquid EC, 40° C. clear yellow glassy — solid, notbirefringent CentriVap off-white, morphology A (small unknown,birefringent amount of material) isopropanol: EC, ambient clearyellowish — water 50:50 solution EC, 40° C. Clear orange glassy — solid,not birefringent CentriVap off-white, morphology A unknown, birefringent

TABLE 10 Capillary Polymorph Screen of Compound 1 by Solvent/AntisolventCrystallization XRPD Solvent Antisolvent Method Habit/Description ResultHFIPA acetonitrile EC Off-white plate, IS blades, and rods, birefringentacetonitrile CentriVap clear and yellow — glassy solid, not birefringent2-butanone precipitation clear glassy solid, not — birefringent ethylacetate precipitation white, morphology A unknown, not birefringentisopropyl precipitation white, morphology A ether unknown, notbirefringent isopropanol EC Clear glassy solid, — not birefringentisopropanol CentriVap clear glassy solid, not — birefringent n-propanolEC clear viscous liquid — n-propanol CentriVap clear and off-white —glassy solid, not birefringent toluene EC clear yellowish — viscousliquid toluene CentriVap clear and yellow — glassy solid, notbirefringent nitromethane EC off-white, unknown A morphology, notbirefringent and needles, birefringent nitromethane CentriVap clear andyellow — glassy solid, not birefringent TFE acetonitrile EC clear stickysubstance — acetonitrile CentriVap off-white, dendridic A formations,birefringent 2-butanone EC clear viscous liquid — 2-butanone CentriVapwhite, dendridic A formations, birefringent ethyl acetate precipitationwhite, morphology A unknown, partially birefringent isopropylprecipitation white, morphology A ether unknown, partially birefringentisopropanol EC yellowish viscous — liquid isopropanol CentriVapoff-white, dendridic A (big formations, crystals birefringent present)n-propanol EC clear solution — n-propanol CentriVap white, dendridic Aformations, birefringent toluene EC off-white, dendridic IS formations,birefringent toluene CentriVap off-white, dendridic A formations,birefringent nitromethane EC off-white, IS morphology unknown, notbirefringent nitromethane CentriVap clear glassy solid, not —birefringent

TABLE 11 Capillary Polymorph Screen of Compound 1 by Vapor Stress XRPDSolvent Habit/Description Result acetone white, morphology A unknown,not birefringent acetonitrile white, morphology A unknown, notbirefringent 2-butanone white, morphology A (MEK) unknown, notbirefringent t-butyl methyl white, morphology A ether (MTBE) unknown,not birefringent ethanol white, morphology A unknown, not birefringentethyl acetate white, morphology A unknown, not birefringent isopropanolwhite, morphology A unknown, not birefringent methanol off-white, Bmorphology unknown, not birefringent toluene white, morphology Aunknown, not birefringent 95% RH white, morphology A unknown, notbirefringent

TABLE 12 Abbreviated Polymorph Screen of Amorphous Compound 1 XRPDSolvent Conditions Habit/Description Result acetone slurry, white,morphology A 7 days unknown, birefringent acetonitrile slurry, white,morphology A, minus 7 days unknown, birefringent one peak acetonitrile:FE clear glassy film, not A, l.c. hexafluoro- birefringent; clear,isopropanol 9:1 morphology unknown, birefringent acetonitrile: SE clearsolution — methanol 4:1 FE yellow glassy film, not — birefringent2-butanone slurry, white, tiny plates, A 7 days birefringent 2-butanone:FE clear glassy film, not IS hexafluoro- birefringent; clear platesisopropanol 9:1 and morphology unknown, birefringent 2-butanone: SEclear light yellow — methanol 4:1 solution FE clear oily film, not ISbirefringent; colorless needles and blades, birefringent ethanol FEclear glassy film, not amorphous birefringent; colorless, morphologyunknown, birefringent RE white, morphology amorphous unknown, notbirefringent ethyl acetate slurry, white, morphology A, minus 7 daysunknown, birefringent one peak ethyl acetate: SE white spherulites ofthin D methanol 4:1 needles, birefringent SE, scale-up yellow needles,D + B birefringent long needles, single B crystal quality a fewneedles + colorless — thin solid film 2410-52-01 + long needles —solvent mixture SE, scale-up clear solution — SE, scale-up clearsolution — SE, scale-up white, long needles — Portion of white, longneedles, B 2482-09-03 birefringent SE, scale-up needles — hexafluoro- FEclear glassy film, not — isopropanol birefringent CP w/ clear solutionwith — acetonitrile small amount of translucent solid CP w/ clearsolution with — 2-butanone small amount of translucent solid CP w/ whiteblades, A ethyl acetate birefringent CP w/ clear solution, very —isopropanol small amount of translucent solid isopropanol slurry, whiteplates and A 7 days blades, birefringent; morphology unknown, notbirefringent isopropanol: SE clear glassy film, not IS hexafluoro-birefringent; colorless, isopropanol 9:1 morphology unknown,birefringent isopropanol: SE clear light yellow — methanol 4:1 solutionFE orange glassy film, not A, l.c. birefringent; colorless, morphologyunknown, birefringent isopropyl ether slurry, white, morphology A 7 daysunknown, not birefringent methanol FE clear glassy film, not amorphousbirefringent; colorless, morphology unknown, birefringent RE white,cracked glassy amorphous film, not birefringent CP w/ white, morphologyB + A isopropyl ether unknown, not birefringent CP w/ white, morphologyD ethyl acetate unknown, not birefringent white precipitate D white,morphology B unknown, not birefringent white, thin needles, B minuspartially birefringent peaks white, morphology B minus unknown,partially peaks birefringent white, morphology B minus unknown,partially peaks birefringent white solid D + B minus peaks white solidD + B minus peaks nitromethane FE clear glassy film, not A birefringent;white blades, birefringent tetrahydro- slurry, off-white, morphology Afuran 7 days unknown, birefringent toluene slurry, white, morphology A 7days unknown, not birefringent toluene: SE clear solution — hexafluoro-FE translucent glassy amorphous isopropanol 9:1 film, not birefringent;orange, morphology unknown, not birefringent toluene: SE clear solution,small — methanol 4:1 amount of white needles and yellow oil FE yellowglassy film, not D birefringent; white, large needles, birefringent2,2,2- FE translucent glassy — trifluoroethanol film, not birefringentwater FE light yellow cracked IS glassy film, not birefringent; lightyellow fibers, birefringent acetone:water slurry, white, morphology A99:1 7 days unknown, not birefringent acetonitrile: slurry, whiteneedles and A water 99:1 7 days morphology unknown, birefringent;morphology unknown, partially birefringent isopropanol: slurry, white,morphology A water 99:1 7 days unknown, partially birefringent

TABLE 13 Vapor Diffusion Experiments on Amorphous Compound 1 XRPDSolvent Antisolvent Time Habit/Description Result hexafluoro- acetone 11days white, morphology IS isopropanol unknown, partially birefringenttetrahydrofuran  7 days white, morphology — unknown, not birefringent2,2,2- acetone 11 days white, morphology IS trifluoro- unknown,birefringent ethanol tetrahydrofuran  7 days white, morphology Aunknown, not birefringent

Example 7

Equilibrium solubilities of Form A in various solvents at roomtemperature are listed in Table 14, below. In each case, the equilibriumsolubility of Form A at room temperature was measured by placing thecompound in excess into different solvents and stirring overnight atambient room temperature, protected from light. Solubility in thefollowing solvents and aqueous buffers was evaluated at roomtemperature: methanol, ethanol, benzyl alcohol, dimethyl sulfoxide,water for injection, bacteriostatic water (containing 0.9% benzylalcohol), 5% dextrose, normal saline (0.9% NaCl), pH 1.1 (glycine HCl),pH 4.2 (glycine HCl), pH 7.1 (phosphate buffer), and pH 9.1 (glycine).Solubilities are reported to the nearest mg/mL unless otherwise stated.

An additional set of solubility samples, were prepared under conditionsthat simulate the human GI tract (pH 1, 0.1 N HCl, pH 4.5 acetatebuffer, pH 7.1 phosphate buffer, pH 9.0 borate buffer). All solutionswere stored overnight in a 37° C. oven, and then filtered through aWhatman 0.45 μm nylon syringe filter to remove insoluble material. Thefiltrate was analyzed by HPLC for strength and the results summarized inTable 14.

TABLE 14 Approximate Solubilities of Form A, at Ambient TemperatureSolubility at R.T. Solubility at 37° C. Solvent (mg/mL) (mg/mL) Methanol2.5 N/T Ethanol 6.1 N/T Benzyl alcohol 85.5 N/T Dimethylsulfoxide >170N/T Water for injection 73.5 N/T Bacteriostatic water (0.9% 86.5 N/Tbenzyl alcohol) 5% Dextrose 61.3 N/T Normal saline (0.9% NaCl) 59.7 N/T0.1N HCl 76.6 100.8 pH 1.1 (glycine HCl buffer) 70.1 N/T pH 4.2 (glycineHCl buffer) 73.8 N/T pH 4.5 (acetate buffer) N/T  99.97 pH 7.1(phosphate buffer) 74.9 N/T pH 9.1 (glycine buffer) 71.1 N/T pH 9.0(borate buffer) N/T 100.6 pH 6.8 (phosphate buffer) N/T 100.7 N/T = “nottested”

1. Form B of Compound 1:

where the compound is in the (R) configuration with respect to thenitrogen, and the compound is substantially free of Form A ofCompound
 1. 2. The compound according to claim 1, characterized in thatthe compound has one or more peaks in its X-ray powder diffractionpattern selected from those at about 7.9, 8.18, 20.3, 21.44, 24.11, and25.12 degrees 2-theta.
 3. The compound according to claim 2,characterized in that the compound has two or more peaks in its X-raypowder diffraction pattern selected from those at about 7.9, 8.18, 20.3,21.44, 24.11, and 25.12 degrees 2-theta.
 4. The compound according toclaim 3, characterized in that the compound has three or more peaks inits X-ray powder diffraction pattern selected from those at about 7.9,8.18, 20.3, 21.44, 24.11, and 25.12 degrees 2-theta.
 5. The compoundaccording to claim 4, characterized in that the compound hassubstantially all of the peaks in its X-ray powder diffraction patternselected from those at about 7.9, 8.18, 10.64, 11.57, 12.68, 13.44,13.89, 14.38, 15.42, 16.01, 16.39, 17.18, 19.89, 20.79, 21.44, 21.9,23.35, 24.49, 24.87, 25.53, and 29.17 degrees 2-theta.
 6. The compoundaccording to claim 5, characterized in that the compound hassubstantially all of the peaks in its X-ray powder diffraction patternselected from: Peak No. °2θ 1 7.9 2 8.18 3 10.64 4 11.57 5 12.68 6 13.447 13.89 8 14.38 9 15.42 10 16.01 11 16.39 12 17.18 13 17.74 14 18.12 1518.47 16 19.37 17 19.89 18 20.3 19 20.79 20 21.44 21 21.9 22 22.31 2323.35 24 24.11 25 24.49 26 24.87 27 25.12 28 25.53 29 26.33 30 26.78 3127.51 32 28.1 33 29.17 34 29.69 35 30.07 36 30.76 37 31.04 38 32.18 3932.88 40 34.33.


7. The compound according to claim 6, characterized in that the compoundhas an X-ray powder diffraction pattern substantially similar to thatdepicted in FIG.
 4. 8-27. (canceled)
 28. Amorphous Compound 1:

where the compound is in the (R) configuration with respect to thenitrogen.
 29. A composition comprising Form A of Compound 1:

where the compound is in the (R) configuration with respect to thenitrogen, further comprising one or more of Form C, Form D, or amorphousCompound 1, and optionally Form B.
 30. The composition according toclaim 29, comprising Form A and amorphous Compound
 1. 31. A composition,comprising at least two of Form B, Form C, Form D, and amorphousCompound
 1. 32. A pharmaceutical composition comprising one or more ofForm A, Form B, Form C, Form D, or amorphous Compound 1, and optionallya pharmaceutically acceptable carrier, adjuvant, or vehicle.
 33. An oralformulation comprising the pharmaceutical composition according to claim32.
 34. An oral formulation comprising a core comprising thepharmaceutical composition according to claim 32, a chelating agent, anda surfactant; and an enteric coat covering.
 35. The formulationaccording to claim 34, wherein the core comprises spheroids, beads, orpellets.
 36. The formulation according to claim 35, wherein the corefurther comprises a carrier, binder, filler, and/or disintegrant. 37.The formulation according to claim 36, further comprising a mucoadhesivecoating comprising the pharmaceutical composition according to claim 32and a mucoadhesive release controlling agent.
 38. An oral formulationcomprising the pharmaceutical composition according to claim 32, whereinthe formulation achieves delivery of the compound in at least twoindependent portions, a first portion being delivered in the stomach,and a second portion being delivered in the upper intestine; wherein theformulation comprises a core comprising the pharmaceutical compositionaccording to claim 32 and a mucoadhesive coating comprising thecomposition and a mucoadhesive release controlling agent, and whereindelivery of the first portion to the stomach is substantially from themucoadhesive coating, and delivery of the second portion to theintestine is substantially from the core.
 39. An oral formulationcomprising a core comprising the pharmaceutical composition according toclaim 32, a chelating agent, and a surfactant; and an enteric coat. 40.The formulation according to claim 39, wherein the core comprisesmultiparticulates, pellets, granules, spheroids or particles and atleast one additional excipient.
 41. The formulation according to claim40, wherein the core comprises a filler or binder or disintegrant. 42.The formulation according to claim 41, wherein the filler or bindercomprises microcrystalline cellulose.
 43. The formulation according toclaim 42, wherein the core further comprises a disintegrant.
 44. Theformulation according to claim 43, wherein the disintegrant iscrospovidone.
 45. The formulation according to claim 44, wherein theprepared cores are in a capsule shell or compressed into tablet form.46-51. (canceled)